Project Summary: Ovarian cancer (OCa) is the fifth leading cause of cancer death for women in the United States. Intrinsically resistant and recurring ovarian cancers are a terminal disease that cannot be cured with existing therapeutics. Considering the molecular and genetic heterogeneity of tumors, we hypothesize that efficacious OCa therapy can be developed by determining the genetic abnormalities found in tumors of individual OCa patients and designing personalized therapy that can overcome patient-specific multi-drug resistance (MDR). We propose to develop robust nanoscale coordination polymers (NCPs) for the co-delivery of front-line and second-line OCa chemotherapeutics (cisplatin or cisplatin plus gemcitabine) and siRNA cocktails targeting MDR genes. A unique endosomal escape mechanism will be elucidated and is expected to be generally applicable to the rational design of nanocarriers for efficient delivery of biologics in vivo. This project will not only provide new fundamental insights nanomedicine research, but also holds great promise for clinical translation for the personalized treatment of resistant OCa. Aim 1: Develop NCP/siRNAs and evaluate their in vitro effects on resistant OCa cell lines. Two NCP/siRNAs formulations with chemotherapeutics in the core and siRNAs targeting MDR in the shell will be developed and characterized. The in vitro gene silencing and cytotoxicity will be evaluated in resistant OCa cells. Aim 2: Evaluate the anticancer efficacy of NCP/siRNAs in orthotopic mouse tumor models of resistant OCa. The general toxicity and anticancer efficacy of NCP/siRNAs will be assessed in mouse models. Aim 3: Actively target NCP/siRNAs by incorporating Her2/neu antibody fragments into the NCP/siRNAs shell. Small protein Her2/neu antibody fragments will be conjugated to a lipid and incorporated into the outer shell of NCP/siRNAs and the resulting nanoparticles will be tested in Her2/neu high expressing and Her2/neu low expressing resistant OCa tumor models to evaluate changes in pharmacokinetics, tumor deposition, and efficacy. Aim 4: Evaluate the anticancer efficacy of NCP/siRNAs and NCP/siRNAs/H2A in patient-derived xenograft (PDX) mouse models of resistant OCa. The expression of MDR-associated genes will be analyzed in OCa tumor PDX samples collected by the Mayo clinic. Personalized therapy will be designed entailing chemotherapeutic agent(s) and the choice of siRNAs targeting MDR genes. Confirmed platinum-resistant tumor cells will be used to evaluate the anticancer efficacy of NCP/siRNAs in orthotopic PDX OCa mouse models. Tumors from Her-2/neu receptor positive and negative patients will be further evaluated for anticancer efficacy by NCP/siRNAs/H2A. Through these aims we seek to establish a new paradigm for the treatment of resistant OCa. NCP/siRNAs can provide personalized therapy for OCa patients and achieve greatly enhanced anticancer efficacy in resistant OCa. As the standards of care for cervical and other cancers, cisplatin-based NCP/siRNAs can have broad impact on treating other resistant cancers.